tbuckley/cabot-search huggingface dataset:
EPID-05. PATTERNS OF RECOMMENDATION FOR SURGICAL INTERVENTION IN GRADE II, III, AND IV ASTROCYTOMAS: IMPLICATIONS FOR DELAYED DIAGNOSIS AND TREATMENT
Authors: Anudeep Yekula, Ping Zhu, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Timely surgical acquisition of tumor tissue for definitive diagnosis forms the foundation for early cancer diagnosis and treatment. Here we examined the pattern of surgical recommendations in the treatment of intracranial astrocytoma. METHODS Grade 2, 3, and 4 astrocytoma (abbreviated as A2, A3, and A4) patients who underwent biopsy for histologic diagnosis were identified in NCDB (2010-2021) and SEER (2004-2019) and divided into those who received recommendation for biopsy on initial presentation and those who received recommendation against surgery but ultimately underwent biopsy. Demographic, clinical characteristics, and survival outcomes of these cohorts were compared. RESULTS In both the NCDB and the SEER, patients ultimately diagnosed with A2 (NCDB: aOR=1.88, p&amp;lt; 0.001; SEER: aOR=1.77, p&amp;lt; 0.001) and A3 (NCDB: aOR=1.97, p&amp;lt; 0.001; SEER: aOR=1.78, p&amp;lt; 0.001) were less likely to receive recommendation for biopsy during initial encounter relative to patients with glioblastoma after adjusting the covariates. Other factors associated with decreased likelihood of recommendation for biopsy included: advanced age, deep cortical/infratentorial location, and smaller tumor size. These findings remain robust after accounting for dehydrogenase (IDH) mutation status, which was available in the NCDB after 2018. In a multivariable model accounting for survival-pertinent variables, including medical comorbidities, A2 (NCDB: aHR=1.23, p=0.006; SEER: aHR=1.15, p=0.039) and A3 (NCDB: aHR=1.44, p&amp;lt; 0.001; SEER: aHR=1.53, p&amp;lt; 0.001) patients who received recommendation against biopsy during initial encounter exhibited worse survival. CONCLUSION Patients with A2 and A3 are more likely to receive recommendation against surgical intervention on initial encounter. The associated survival pattern bears relevance to the potential impact of delayed diagnosis and treatment.
NIMG-21. SERIAL QUANTITATIVE MRI RADIOMICS SIGNATURE FOR PREDICTION OF SURVIVAL IN GLIOBLASTOMA – A PILOT STUDY
Authors: Cecil Chen, Philip Martin, Eng-Siew Koh, Caterina Brighi, Farhannah Aly, Robba Rai, Lois Holloway, Peter Metcalfe, Sugendran Pillay
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Radiomics in glioblastoma (GBM) imaging incorporates mathematical and statistical quantification of complex imaging features as surrogate biomarkers of tumour physiology. Delta-radiomics extends this capability by monitoring changes in these features over time. This study aims to evaluate selected radiomic and delta-radiomic features of diffusion-weighted imaging (DWI) as potential early predictors of overall survival (OS) in GBM patients undergoing adjuvant chemo-radiotherapy (aCRT). METHODS Imaging and data from n=12 newly diagnosed GBM patients prospectively recruited at Liverpool Hospital, New South Wales, were retrospectively analysed. Patients underwent serial MRI via 3.0T Siemens Magnetom-Skyra scanner, including anatomical and DWI sequences, before aCRT (baseline), and at 3 (FU1) and 6 weeks (FU2) post aCRT commencement. Gross tumour volume (GTV) was manually segmented on contrast-enhanced T1-weighted images. Four first-order histogram radiomic features (mean, skewness, entropy and 10th-percentile) and volume were extracted from the GTV on DWI sequences at each timepoint. Delta-radiomic features were calculated from the difference between measurements at baseline and each follow-up. Linear correlation between OS versus baseline and delta-radiomic features were calculated with Pearson’s coefficient (r). Statistically significant correlations were tested on an external validation dataset of n=8 GBM cases from The Cancer Imaging Archive (ACRIN-FMISO-Brain and ACRIN-DSC-MR-Brain datasets). RESULTS A significant positive correlation was found between OS and delta-entropy at FU2 (r = 0.639, p = 0.02). No significant correlation was found between OS and baseline or delta mean, skewness, or 10th percentile (p &amp;gt; 0.05). No significant correlation was found between OS and delta-volume at FU1 (r = 0.134, p = 0.68) or FU2 (r = 0.100, p = 0.76). CONCLUSION Our results indicate a potential utility of delta-entropy for prediction of overall survival. RESULTS will be validated on an external dataset. Further evaluation of radiomic and delta-radiomic features on a larger sample size is warranted.
ANGI-08. COMPREHENSIVE ANALYSIS OF MECHANISM OF GLIOBLASTOMA INVASION USING PATIENT DERIVED XENOGRAFT MODELS
Authors: Noriyuki Kijima, Tetsuro Tachi, Hideki Kuroda, Koki Murakami, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Haruhiko Kishima
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) has a poor prognosis despite intensive treatments such as surgical resection, radiation, and chemotherapy, thus new therapeutic strategies are urgently needed to improve the outcome. In addition, invasive nature of glioblastoma is one of the reasons for treatment failure, thus regulating glioblastoma invasion is essential to improve the outcome of GBM patients. To develop new treatment strategies, patient derived xenografts (PDXs) are essential tools for preclinical and translational research for glioblastoma because PDXs recapitulated histological features of original patients’ tumors such as invasion. In this study, we aim to comprehensively analyze the mechanism of glioblastoma invasion using PDXs. We have injected GFP-tagged glioblastoma PDXs lines into the right cerebrum of immunodeficient mice and dissected the right and left cerebrum separately when the mice got tumors. We dissociated the brain, sorted tumor cells by flow cytometry, and extracted RNA from tumor cells in right and left cerebrum, respectively. We performed RNA sequencing and analyzed the transcriptome differences between tumor cells from right cerebrum and left cerebrum. We found significant differences in expression of extracellular matrix related proteins, cell motility related proteins, and cell adhesion related proteins between these two. These findings suggest that PDXs will be of use for comprehensively investigating the mechanism of glioblastoma invasion and extracellular matrix related proteins, cell motility related proteins, and cell adhesion related proteins have significant roles of glioblastoma invasion.
IMMU-06. THE ROLE OF BRAIN TUMOR MICROENVIRONMENT ON T CELL TELOMERE SHORTENING
Authors: Gustavo Ignacio Vazquez Cervantes, Joshua Katz, Aurora Lopez-Rosas, Yu Han, Catalina Lee-Chang, Jason Miska, Maciej Lesniak
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma (GBM) stands as the most frequent and the most aggressive of the primary brain tumors. GBM-driven immunomodulatory mechanisms induce T-cell exhaustion or senescence leading to impaired anti-tumor responses. Telomeres are nucleoprotein complexes located at the ending regions of eukaryotic chromosomes that become shorter during each cell cycle or due to cellular stress leading to DNA damage response and cell cycle arrest. Tumor-associated T-cell senescence associated with telomere loss on different tumor models still represents a barrier to the success of T-cell-based tumor immunotherapies. However, the mechanisms through which the GBM microenvironment promotes T-cell telomere loss remain poorly understood. METHODS We evaluated the expression profile of telomere maintenance-related gene sets of single-cell RNA sequencing from public datasets of GBM patients matched with the peripheral blood. We determined the telomere length, telomere-associated DNA secondary structures (G-quadruplex), β-galactosidase activity, and reactive oxygen species (ROS) production of CD8+ T-cells after 72 h exposure to the conditioned media of malignant glioma murine cell cultures CT2A and GL261. We analyzed the telomere length and G-quadruplex abundance in peripheral and tumor-infiltrated T-cells at different time points of tumor-bearing mice injected with CT2A and GL261 cells. RESULTS CD8+ T-cells exposed to the malignant cell conditioned media showed a 20 % reduction of telomere length compared to controls (p&amp;lt; 0.05), a 1.5-fold increase of β-galactosidase activity (p&amp;lt; 0.05), and a 2-fold increase of ROS production (p&amp;lt; 0.05). Both tumor-infiltrated CD4+ and CD8+ T-cells presented a relative telomere shortening of 22 % compared to spleen CD4+ and CD8+ T-cells (p&amp;lt; 0.05). Besides, G-quadruplex abundance increased by 5-fold in tumor-infiltrated CD4+ and 3-fold in tumor-infiltrated CD8+ T-cells compared to peripheral T-cells (p&amp;lt; 0.05). CONCLUSIONS T-cell telomere maintenance is affected by malignant cell conditioned media. In vivo tumor microenvironment induced telomere shortening of tumor-infiltrated T-cells in a time-dependent fashion.
CSIG-04. INTEGRATED MOLECULAR AND FUNCTIONAL CHARACTERIZATION OF THE INTRINSIC APOPTOTIC MACHINERY IDENTIFIES A DIAGNOSTICALLY INFORMED THERAPEUTIC APPROACH FOR MALIGNANT GLIOMA
Authors: Elizabeth Fernandez, Wilson Mai, Kai Song, Nicholas Bayley, Jiyoon Kim, Henan Zhu, Linda Liau, Gang Li, William Yong, Andrew Souers, Jingyi Jessica Li, Thomas Graeber, Timothy Cloughesy, David Nathanson
Journal: Neuro-Oncology (2023)

Abstract Molecular profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, has emerged as an alternative method to anticipate drug responses. Here we performed combined molecular and functional characterization (via BH3 profiling) of the intrinsic apoptotic machinery in glioma patient samples and derivative models. We identified that standard of care treatment rewires the apoptotic machinery in a genotype specific manner, revealing targetable vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling uncovered that high mitochondria priming was also required to induce tumor apoptosis. Accordingly, a composite molecular and functional signature best predicted responses of diverse intracranial glioma models to standard of care combined with a new clinical drug targeting the intrinsic apoptotic machinery. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death.
BIOS-07. SURVIVAL TIME OF GLIOBLASTOMA PATIENTS ENROLLED IN RANDOMIZED CONTROLLED TRIALS: A NEXT GENERATION META-ANALYSIS OF SURVIVAL CURVES
Authors: Farrukh Hameed, Omar Sajjad, Sam Sathyamurthi, Mamindla Priyadarshini, Katamon Klaichart, Aaliyah Thompson, Tanvi Hegde, Yan Wang, Pascal Zinn
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma is the most common primary malignant brain tumor and remains an incurable disease with high mortality. Randomized controlled trials (RCTs) have investigated novel therapies that have shown promise, but there have been no major additions in the treatment armamentarium in almost two decades. OBJECTIVE In a first study of its kind, we investigate the cumulative change in survival times over years for GBM patients by combining the survival outcome data published by multiple trials. METHODS A systematic database search of PubMed for GBM RCTs with significant outcomes published after 2005 was conducted. All Kaplan-Meier (KM) survival curves were analyzed. Individual patient data was extracted from the survival curves and a cumulative survival curve was generated with corresponding times calculated. The primary outcome for all included RCT was mortality at longest follow-up. RESULTS We identified 14 RCT which contained KM curves presenting sufficient data for individual patient survival data extraction. Survival data of a total of 2294 patients was extracted with 1396 (60.85%) patients in the treatment arms and 898 in the control arms (39.15%). Patients in the control arm received the standard care of GBM management, whereas those in the treatment arms received differing experimental regimens. After generating the cumulative survival curve, the median survival time for patients in the treatment arm was found to be 15.2 months and 11.2 months for the control arm (P &amp;lt; 0.0001). The two-year survival rate was 31.0% for the treatment arm and 15.6% for the control arm. CONCLUSION The survival times observed in GBM patients receiving the standard care of management were worse than anticipated. In general, however, overall estimates of survival among patients with GBM have improved with more patients surviving to 2 years.
DNAR-06. RHO GTPASES AS A POTENTIAL CHEMOSENSITIZER OF TMZ AND CISPLATIN-RESISTANT GBM TUMOR CELLS THROUGH A P53-DEPENDENT MECHANISM
Authors: Fabio Forti, Yuli Magalhaes
Journal: Neuro-Oncology (2023)

Abstract Rho GTPases regulate cellular processes related to tumor progression and their expression/activity determines the invasiveness and aggressiveness of GBM and, despite current aggressive therapies, effective treatments remain desired. Here we proposed that Rho GTPase acts on the genomic stability of GBM and its resistance to TMZ and cisplatin drugs in a p53-dependent mechanism. We selected GBM cell lines with different p53 status – U87-MG and A172 (wt-p53), T98G and U138-MG (mut-p53) – and subjected them to Rho inhibition by C3 toxin and subsequent DNA damage by TMZ treatments or cisplatin. Bioinformatic analysis showed that prolonged exposure to cisplatin induces the transcription of regulatory genes of Rho GTPases. Pulldown assays corroborated this analysis showing an increase in Rho activity after exposure to cisplatin or TMZ. IC50 for TMZ and cisplatin, as well as survival and proliferation assays, were all decreased by Rho inhibition in wt-p53 cells, while HCR assays showed that DNA repair capacity for both genotoxic drugs is decreased by Rho inhibition only in wt-p53 cells. To verify the role of p53 in this mechanism, we knocked down p53 in U87-MG cells, thus avoiding Rho inhibition-induced chemosensitivity and impaired DNA repair. Then, U87-MG cells were subjected to various treatment regimens with low doses of TMZ or cisplatin to obtain a subpopulation of cells resistant to these drugs. Further exposure to DNA damage led to increased p53(Ser15) phosphorylation, p53 nuclear translocation, and F-actin-induced polymerization. Two TMZ-resistant cell clones were selected, both showing a significant increase in TMZ IC50 for survival, while Rho inhibition reduced IC50 in both clones, significantly reversing the acquired resistance of these cells. These results suggest that Rho GTPase plays a role in DNA repair and in the acquired GBM wt-p53 resistance to TMZ and show that this pathway may be a fragile-point against current therapies.
CSIG-07. HYPERCELLULAR NODULES IN OLIGODENDROGLIOMA REPRESENT POCKETS OF PROLIFERATIVE STEM-LIKE TUMOR CELLS
Authors: Mengyi Liu, Karen Abramson, Emily Hocke, Stephanie Hilz, Joseph Costello, Roger McLendon, David Ashley, Simon Gregory, Giselle Lopez
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Oligodendrogliomas are a progressive, infiltrative glioma. By histology, a subset of oligodendrogliomas demonstrate hypercellular nodules (HCN), which often have increased anaplasia compared to surrounding tumor. However, the signals driving anaplasia are unknown. METHODS We first performed a GeoMX 89-protein Digital Spatial Profiling (DSP, Nanostring) panel on a cohort of ten oligodendrogliomas with HCN., followed by spatial whole RNA transcriptome analysis (10x Genomics Visium) on six oligodendrogliomas. For the latter, following unsupervised clustering, we performed Gene Ontology (GO) enrichment analysis and Ingenuity Pathway Analysis (IPA, Qiagen) on the differentially expressed genes between HCN and adjacent tumor. We performed paired single nucleus RNA sequencing for deconvolution of the spatial transcriptomic data. RESULTS AND CONCLUSIONS By protein DSP, we identified a marker of stemness (OLIG2) and a proliferation marker (Ki-67) as present at increased levels (p&amp;lt; 0.05) within HCN. We subsequently performed spatial whole transcriptome analysis. On unsupervised clustering of differentially expressed genes, the HCN spots cluster away from the remaining tumor spots, supporting a distinct niche. GO and IPA both identified increased activity in several central nervous system developmental pathways, providing further evidence for the “precursor-like” state of cells in HCN. We then annotated paired single nucleus RNA sequencing results to align tumor cells with astrocytic-like, oligodendroglial-like, and stem-like cell states. Using this to deconvolute the spatial transcriptomic data, we found that the vast majority of HCN are enriched for either stem-like or OC-like/stem-like tumor cells. Taken together, the findings support HCN as niches for the most precursor-like, proliferative oligodendroglial cells.
EPCO-18. HETEROCHROMATIN DYSFUNCTION IMPACTING GENOMIC TOPOLOGY AND SUPERENHANCER LANDSCAPES PROMOTES ATRX-DEFICIENT GLIOMAGENESIS
Authors: Prit Benny Malgulwar, Ajay Kumar Saw, Anand Singh, Carla Danussi, Sharvari Dharmaiah, William E Johnson, Kunal Rai, Jason Huse
Journal: Neuro-Oncology (2023)

Abstract Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in diffuse gliomas. Whether and how ATRX deficiency promotes oncogenesis remains unclear, despite its implication across a broad array of physiological processes. We sought to delineate the molecular mechanisms by which global epigenomic dysfunction promotes oncogenic phenotypes in ATRX-deficient glioma models. Building on earlier work implicating chromatin accessibility and transcriptional shifts, we employed integrated epigenomic profiling in Atrx-intact and -deficient murine neuroepithelial progenitor cells (mNPCs), validating findings will functional approaches in human glioma stem cells (GSCs) of appropriate genotype. We found that ATRX deficiency dramatically impacted the integrity of large heterochromatin domains genome-wide, with tangible effects on underlying gene expression. This process fundamentally altered chromatin topology, as assessed by Hi-C analysis, and associated superenhancer landscapes, influencing key developmental gene sets like the HOXA cluster. Pharmacological inhibition of HOXA signaling in GSCs selectively reduced proliferation, increased apoptosis, and impaired in vivo growth in the ATRX-deficient context. Finally, our results pointed to derepression of LINE1 endogenous retroviral elements as key mediators of ATRX-deficient heterochromatin dysfunction. Our work implicates novel and targetable molecular mechanisms involving complex epigenomic rewiring and chromatin topology in ATRX-deficient oncogenesis. In doing so, we advance the understanding of a deadly brain tumor along with broader conceptions of epigenetic mechanisms as fundamental drivers in cancer.
BIOM-19. PLASMA EXTRACELLULAR VESICLE SAMPLING FROM HIGH GRADE GLIOMA PATIENTS DEMONSTRATES A SMALL RNA SIGNATURE INDICATIVE OF DISEASE AND IDENTIFIES LNCRNA RPPH1 AS A HIGH GRADE GLIOMA BIOMARKER
Authors: Jae Ho Han, Gabriel Wajnberg, Kathleen Attwood, Brandon Hannay, Robert Cormier, Simi Chacko, Syndey Croul, Maya Wilms, Matthias Schmidt, Andrea Hebb, Mary MacNeil, Jeremy Roy, Adrienne Weeks
Journal: Neuro-Oncology (2023)

Abstract High grade gliomas (HGGs) and cells of the tumour microenvironment (TME) secrete extracellular vesicles (EVs) into the plasma that contain genetic and protein cargo which function in paracrine signaling. Isolation of these EVs and their cargo from plasma could lead to a simplistic tool that can inform on diagnosis and disease course of HGG. In the present study, plasma extracellular vesicles (EVs) were captured utilizing a peptide affinity method (Vn96 peptide) from high grade glioma (HGG) patients and normal controls followed by next generation sequencing (NovaSeq6000) to define a small RNA (sRNA) signature unique to HGG. Over 750 differentially expressed sRNA (miRNA, snoRNA, lncRNA, tRNA, mRNA fragments and non-annotated regions) were identified between HGG and controls. MiEAA 2.0 pathway analysis of the miRNA in the sRNA signature revealed miRNA highly enriched in both EV and HGG pathways demonstrating the validity of results in capturing a signal from the TME. Also revealed were several novel HGG plasma EV sRNA biomarkers including lncRNA RPPH1 (Ribonuclease P Component H1), RNY4 (Ro60-Associated Y4) and RNY5 (Ro60-Associated Y5). Furthermore, in paired longitudinal patient plasma sampling, RPPH1 informed on surgical resection (decreased on resection) and importantly RPPH1 increased again on clinically defined progression. The present study supports the role of plasma EV sRNA sampling (and particularly RPPH1) as part of a multi-pronged approach to HGG disease course surveillance.
DDDR-19. FIRST-IN-CLASS CANCER THERAPEUTICS TARGETING THE DNA DAMAGE RESPONSE
Authors: Adam Robertson, Terezia Prikrylova, Hope Lancero, Christy Wilson, Claudia Petritsch
Journal: Neuro-Oncology (2023)

Abstract Hemispherian is advancing first-in-class therapeutics for cancers that are historically difficult to treat. Glioblastoma multiforme (GBM) is the primary indication for our lead compound GLIX1, which is currently in late-stage preclinical development. GLIX1 is developed together with a biomarker-based companion diagnostic assay to pair diagnostics and optimal treatment. It is Hemispherian’s mission to provide superior treatment options for brain cancer patients. Hemispherian’s proprietary molecules selectively target the DNA damage response in cancer cells. These molecules take advantage of a pre-existing condition of all cancer cells – nearly all cancer cells have a reduction in levels of the DNA base modification, 5-hydroxymethylcytosine. Hemispherian scientists have found that restoration of this base modification to normal cells activates the DNA damage response resulting in cancer cell death. Targeting of the enzyme responsible for maintaining genomic 5-hydroxymethylcytosine, TET2, led to the discovery of the GLIX family of molecules. Hemispherian’s lead GLIX molecules, GLIX1 and GLIX5, show excellent efficacy in vivo in xenograft models, have a superior safety profile, are orally bioavailable and are blood brain barrier penetrant. GLIX efficacy against a panel of patient-derived cell lines representing a broad spectrum of pediatric and adult brain tumor diagnoses will be discussed. Taken together, these molecules have an exceptional profile for treating a broad range of cancers including cancers of the brain.